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Abstract

Background—This study tested the hypothesis that rate-adaptive atrial pacing would prevent paroxysmal atrial fibrillation (PAF) in patients with frequent PAF in the absence of symptomatic bradycardia.

Methods and Results—Patients (n=97) with antiarrhythmic drug-refractory PAF received a Medtronic Thera DR pacemaker 3 months before planned AV node ablation. Patients were randomized to no pacing (n=48) or to atrial rate-adaptive pacing (n=49). After a 2-week stabilization period, patients were followed up for an additional 10 weeks. The time to first recurrence of sustained PAF, the interval between successive episodes of PAF, and the frequency of PAF were compared between the 2 groups in intention-to-treat analysis. Time to first episode of sustained PAF was similar in the no-pacing (4.2 days; 95% CI, 1.8 to 9.5) and the atrial-pacing (1.9 days; 95% CI, 0.8 to 4.6; P=NS) groups. PAF burden was lower in the no-pacing (0.24 h/d; 95% CI, 0.10 to 0.56) than in the atrial-pacing (0.67 h/d; 95% CI, 0.30 to 1.52; P=0.08) group. Paired crossover analysis in 11 patients revealed that time to first PAF was shorter during atrial pacing (1.6 days; 95% CI, 0.6 to 4.9) than with no pacing (6.0 days; 95% CI, 2.4 to 15.0; P=0.13), and PAF burden was greater during atrial pacing (1.00 h/d; 95% CI, 0.35 to 2.91) than with no pacing (0.32 h/d; 95% CI, 0.09 to 1.13; P<0.016).

Conclusions—Atrial rate-adaptive pacing does not prevent PAF over the short term in patients with antiarrhythmic drug-resistant PAF without symptomatic bradycardia.

The present study was designed to test the hypotheses that (1) atrial-based pacing reduces the time to first recurrence of sustained PAF and (2) atrial-based pacing reduces the frequency and duration of PAF.

Methods

Study Population

Patients with a history of PAF who had experienced at least 3 episodes of PAF within the year before study were enrolled. The most recent episode occurred within 3 months of entry. At least 1 of these episodes of PAF was documented electrocardiographically. Patients were refractory to or intolerant of medical therapy and were being considered for total AV node ablation.

Study Protocol

The study design is outlined in Figure 1⇓. Consenting patients received a Medtronic Thera DR pacemaker 3 months before planned AV node ablation. This device can store information on the time, date, and duration of up to 15 consecutive episodes of an atrial tachyarrhythmia. This information can be retrieved during follow-up visits. After implantation of the pacemaker, patients were randomly assigned to no pacing or to atrial pacing. The DDI mode at a rate of 30 bpm was used for no pacing. The DDI mode allowed the high-rate atrial episode diagnostic feature used for detection of PAF. The DDIR mode with a lower rate of 70 bpm was used for atrial pacing. This mode likewise activated the high-rate atrial episode diagnostic feature, and the lower rate and rate responsiveness were chosen to ensure that the atrium would be paced most of the time. Detailed pacemaker programming parameters used are shown in Table 1⇓.

Study protocol. Patients were randomized to receive a dual-chamber rate-adaptive pulse generator with ability to store information on time, date, and duration of up to 15 consecutive episodes of a high-rate atrial event. Patients were randomized to no pacing or to atrial pacing, and their devices were programmed to DDI rate 30 bpm mode or DDIR lower-rate 70 bpm mode, respectively. After a 2-week stabilization period to allow lead maturation, diagnostic data were retrieved by telemetry and diagnostic counters were cleared. Some patients crossed over early to atrial pacing because of recurrence of highly symptomatic PAF. Patients were reassessed 3 months after pacemaker implantation, and diagnostic data used for analysis of study outcome events were retrieved by telemetry. At this point, untreated patients could cross over to atrial pacing and be followed up for an additional 3 months, including a 2-week stabilization period. AV node ablation was considered after completion of study protocol.

Patients completed a 2-week stabilization phase to reduce the probability that short-term lead placement might increase arrhythmia frequency and to permit stabilization of antiarrhythmic drug therapy. High-rate atrial episode diagnostic data were retrieved and the counters cleared at 2 weeks. The next follow-up visit was scheduled 3 months after pacemaker implantation. At that visit, high-rate atrial episode data were retrieved. These data were used to determine the primary outcome event. Patients in the no-pacing group could cross over to a trial of atrial pacing after the 3-month follow-up period or earlier if they experienced intolerable recurrent symptomatic PAF. On completion of the 3-month follow-up, patients either proceeded to AV node ablation or could defer the procedure. Ambulatory ECGs were obtained at baseline and at 3 months.

Study Outcome Events

The primary study outcome was the time to first recurrence of PAF lasting ≥5 minutes occurring ≥2 weeks after randomization. Because the time course of recurrence may not be completely random, the interval between the first and second episodes of PAF was also determined.18 Other outcome measures included intervals between successive episodes of PAF, frequency of PAF, and proportion of patients who chose to defer ablation.

PAF Detection

The Thera DR high-rate atrial tachycardia detection feature was used for PAF detection in this study. This feature has been reported to have a high sensitivity and specificity for the detection of atrial tachyarrhythmias.19 The programming parameters for PAF detection (Table 1⇑) were selected to reduce the likelihood that nonsustained PAF would fill the diagnostic counters and to ensure that intermittent sense failure of atrial events during PAF would not be inappropriately classified as PAF.19 No PAF episodes <1 minute long were detected as an episode of PAF. To maximize collection of sequential episodes of PAF, the atrial electrogram storage feature was not used. Validation of appropriate detection of PAF was carried out in 28 patients by use of an enhanced marker channel feature of the device combined with ambulatory ECG. One channel of the ambulatory ECG and downloaded marker signals representing what the device interpreted as atrial and ventricular electrograms were recorded simultaneously. Appropriate detection of all episodes of PAF was observed in 10 patients who experienced PAF during ambulatory ECG monitoring.

False-positive detection of PAF by the Thera DR could occur because of oversensing of near-field P waves or far-field R waves or competitive atrial pacing when the atrial rate is high and the postventricular atrial refractory period is long.202122 To exclude false-positive detections of PAF, all episodes of PAF detected by the pulse generator were reviewed by 2 observers who were blinded to the programmed pacing modality.22 Episodes designated as oversensing or competitive atrial pacing were then reviewed by an additional 2 observers for a final classification. Of 1636 episodes of PAF detected in the study population, 48 (2.9%) were inappropriately detected as PAF. There were 25 inappropriate detections (1.5%) due to oversensing; 2 of 3 patients with oversensing had unipolar atrial leads. Twenty-three episodes of competitive atrial pacing (1.4%) occurred in 7 patients. False-positive detections were not included in the final data analysis.

Data Analysis

Analysis was performed according to the intention-to-treat principle. The times to occurrence of the first and second episodes of PAF were determined by the Kaplan-Meier method.23 Differences in the curves were compared by the log-rank test.24 Differences between curves for paired data were compared by a Cox proportional hazards model incorporating the cluster term. PAF burden was calculated as the total duration of atrial fibrillation during the follow-up period. When the event counters were filled, PAF burden was calculated as the total duration of atrial fibrillation during the time available for analysis. Geometric mean data were calculated after log transformation, and differences were compared by a nonpaired t test. Differences in proportions were compared a χ2 analysis. Data are presented as mean±SD or geometric mean and 95% CIs when log transformation was used. A value of P<0.05 for 2-sided comparisons was considered significant.

Results

Study Population

Forty-eight patients were randomized to the no-pacing group and 49 to the atrial-pacing group. The characteristics of the 2 groups were similar and are shown in Table 2⇓. At the 3-month follow-up visit, pacing had not occurred in either chamber in the no-pacing group, whereas the atrium was paced 67±34% of the time and the ventricle was paced 64±31% of the time in the atrial-pacing group. Ambulatory ECG recordings indicated that 67% of pacing in the ventricle was competitive.

Early Crossovers to Atrial Pacing or AV Node Ablation

Twelve patients randomized to no pacing crossed over to atrial pacing before completion of the 2-week stabilization period. AV node ablation was performed before completion of the 3-month follow-up period in 12 patients (25%) randomized to no pacing and in 17 patients (35%) randomized to atrial pacing. Eleven patients completed trials of no pacing and subsequent atrial pacing. AV node ablation was deferred in 14 patients (29%) in each group.

Intention-to-Treat Analysis

Survival free of recurrent PAF after the 2-week stabilization period is shown in Figure 2⇓. No significant differences were observed between the 2 groups (P=0.26). Event-free survival of the interval between the first and second episodes of sustained AF was also compared and was similar between the 2 groups (Figure 3⇓).

Event-free survival to first episode of sustained PAF in patients randomized to no-pacing therapy (dashed line, n=48) or to atrial-pacing therapy (solid line, n=49). Analysis was performed on the basis of intention to treat.

Event-free survival between first and second episodes of sustained PAF in patients randomized to no-pacing therapy (dashed line, n=48) or to atrial-pacing therapy (solid line, n=49). Analysis was performed on the basis of intention to treat.

The characteristics of PAF are shown in Table 3⇓. The majority of patients (84%) experienced PAF, and most patients experienced multiple episodes. No significant differences in the time to first episode of PAF, the interval between first and second episodes of PAF, the number of episodes of PAF, or the rate of PAF were observed. The total PAF burden tended to be lower in the no-pacing group than in the atrial-pacing group (P=0.08). The interval between the first and second episodes of PAF was significantly shorter than the time to first episode of PAF in both groups (P<0.05).

Analysis of PAF recurrence immediately after pacemaker implantation was also performed. The time to first episode of PAF occurring during the 2-week stabilization period before the occurrence of any patient crossovers to atrial pacing was similar in the no-pacing (4.6 days; 95% CI, 2.4 to 7.1) and the atrial-pacing (2.4 days; 95% CI, 1.7 to 3.0; P=0.16) groups. The interval between first and second episodes of PAF occurring during the 2-week stabilization period was also similar in the 2 groups.

Ambulatory ECG monitoring demonstrated that atrial pacing reduced the frequency of SVPBs (3.8/h; 95% CI, 1.4 to 10.9 at baseline, to 0.5/h; 95% CI, 0.2 to 1.1 at 3-month follow-up; P<0.01), whereas SVPB frequency was unchanged in the no-pacing group over time (3.2 SVPB/h; 95% CI, 0.9 to 11.9 at baseline and 3.2 SVPB/h; 95% CI, 0.8 to 12.6 at 3-month follow-up; P=NS).

Paired Crossover Data

Eleven patients completed the 3-month follow-up in the no-pacing limb and then crossed over to a 3-month trial of atrial pacing. Event-free survival to the first episode of PAF and between the first and second episodes of PAF is shown in Figure 4⇓. PAF tended to recur earlier during atrial pacing than with no atrial pacing. The characteristics of PAF during follow-up in the 2 treatment modes are shown in Table 4⇓. The time to first PAF tended to be shorter during atrial pacing than with no pacing (P=0.13). The total PAF burden was significantly greater during atrial pacing than with no pacing (P=0.016).

Top, Event-free survival to first episode of sustained PAF in 11 patients who completed a trial of no-pacing therapy (dashed line) and then completed a trial of atrial-pacing therapy (solid line). Bottom, Event-free survival between first and second episodes of PAF in 11 patients who completed a trial of no pacing (dashed line) and then a trial of atrial pacing (solid line).

Discussion

Present therapeutic strategies for the management of PAF are unsatisfactory for many patients. Recently, atrial-pacing modalities have been proposed for the prevention of PAF.345 To the best of our knowledge, the present study is the first to test the hypothesis that atrial pacing might prevent or reduce the burden of PAF in patients without symptomatic bradycardia. The results show that atrial rate-adaptive pacing does not prevent PAF recurrence, nor does atrial pacing reduce the frequency or duration of PAF over the short term after implantation of a DDDR pacemaker in patients without symptomatic bradycardia.

Coumel et al1 reported that atrial pacing prevented vagally mediated PAF in 4 of 6 patients as long as a sufficient pacing rate was maintained. Attuel et al2 reported that DDD pacing with the lower rate programmed to exceed the diurnal mean heart rate prevented PAF in 10 patients with sinus node disease in whom PAF was associated with bradycardia or atrial pauses. Other such data have been reviewed.3 Saksena et al4 reported that single- and dual-site right atrial pacing prolonged the PAF-free interval compared with the preimplant interval in patients with sinus node disease and PAF. Some of these studies were not prospective, drug therapy before and after pacing was not carefully controlled, and therapy was not randomly assigned. Moreover, all patients had bradycardia as an indication for pacing. In the present study, a no-pacing treatment group was possible because the study population did not require pacing for bradycardia and patients were stabilized on antiarrhythmic drug therapy during the 2-week run-in phase.

Mechanisms for Pacing Prevention of PAF

Atrium-based pacing might prevent PAF by preventing bradycardia-dependent episodes of PAF. Bradycardia-induced increased dispersion of atrial repolarization may provide a substrate for PAF.36725 We hypothesized that atrial pacing might prevent PAF by preventing “relative” bradycardia-induced changes in atrial electrophysiology. In our study population randomized to atrial pacing, the atrium was paced 67% of the time. If consistent atrial activation is important, selection of a higher lower rate for pacing would have increased the proportion of time the atrium was paced and might have altered the time course of PAF recurrence. However, other investigators evaluating an algorithm that ensures almost constant atrial pacing have not shown a significant reduction in the frequency of PAF.26 Furthermore, episodes of PAF documented during ambulatory ECG monitoring were frequently observed during atrial pacing in our patients.27

Atrial overdrive suppression of SVPBs has also been postulated to be a mechanism for prevention of PAF.358 A pacing algorithm to suppress SVPBs in patients with PAF has been reported to prevent PAF in some patients but to increase PAF recurrence in other patients.5 In our study population, atrial pacing did suppress SVPB frequency, but this did not correlate with a reduction in PAF.27

More rapid atrial pacing might provoke atrial arrhythmias, as has been suggested by the paired crossover data analysis in the present study. It is possible that an aggressive rate-response algorithm could initiate episodes of rapid atrial pacing, leading to atrial fibrillation. During ambulatory ECG monitoring, we never observed episodes of atrial pacing at the upper sensor rate provoking atrial fibrillation.27 Competitive atrial pacing resulting in short atrial-pacing intervals due to programming a long postventricular atrial refractory period might initiate PAF. However, we saw no evidence of this during ambulatory ECG monitoring.

It may be that atrial pacing per se has no direct antiarrhythmic effects. Atrioventricular pacing may allow more aggressive antiarrhythmic therapy, because symptomatic sinus bradycardia or high-grade AV block is no longer a concern. Furthermore, it is possible that ventricular pacing may be proarrhythmic by virtue of the deleterious effects of ventricular pacing on cardiac hemodynamics, which might cause asynchronous ventricular activation,28 valvular regurgitation,1112 and stretch-induced changes in atrial repolarization that might predispose to PAF.7910

Possible Limitations

The high proportion of early crossovers to atrial-pacing therapy reduces the power of this study. Thus, it is possible that a modest treatment effect of atrial pacing would not be detected. However, because patients in the atrial-pacing group were experiencing PAF earlier than the no-treatment group, such an outcome is unlikely.

The majority of atrial leads were positioned in the right atrial appendage. It is possible that stimulation in this site results in delayed activation of some areas in the atria that are important in the initiation of PAF. Site-specific atrial pacing, eg, Bachmann’s bundle,2930 left atrial, or dual-site atrial pacing,431 might be more efficacious by virtue of shortening total atrial activation times. These modalities are currently being tested. As discussed, it is possible that more continuous atrial pacing might prevent PAF, because the patients in the present study were not paced in the atrium 33% of the time. Other studies are currently testing algorithms to promote more continuous pacing. The present study compared no pacing with atrial pacing in the DDIR mode. In the DDIR mode, ventricular rate acceleration is not dependant on the atrium. Hence, the present study results cannot necessarily be extrapolated to other pacing modalities. The primary study outcome depended on reliable detection of PAF by the device. It is possible that undersensing of PAF occurred in some patients; however, the frequency should have been similar in both groups. The study design did not discriminate between symptomatic and asymptomatic episodes of PAF.

Conclusions

Atrial rate-adaptive pacing does not prevent recurrence of PAF over the short term, nor does it reduce PAF frequency or duration in patients with PAF in the absence of symptomatic bradycardia.

Appendix A1

The following institutions and individuals participated in this study (listed in descending order of number of patients randomized).

Footnotes

All the authors have been involved in the clinical evaluation of Medtronic investigational devices in the past. Dr Gillis has been a member of a Medtronic Physician Advisory Board. Dr Yee is currently a member of the Medtronic Physician Advisory Board.